The radioactive diagnostic imaging agent is a medicine directly administered to a human body and is a pharmaceutical composition containing a compound labeled with a specific radioisotope as an effective ingredient. The radioactive diagnostic imaging agent enables diagnosis by administering an agent to a subject and detecting a radiation emitted from the compound, followed by imaging based on information obtained from the radiation. The thus-conducted diagnosing method is referred to as nuclear medicine examination, and is effective in diagnosing a variety of diseases including heart disease and cancer. Also, nuclear medicine examination is characteristic in that it has not only high specificity and sensitivity to diseases, but also has an advantage of providing information on the functionality of lesions, compared to other examination techniques.
Compounds which are researched and developed for radioactive diagnostic imaging agents include 3-[18F]fluoro-1-aminocyclobutanecarboxylic acid (hereinafter referred to as [18F]FACBC). It is known that [18F]FACBC is taken up into a cell via an amino acid transporter. Thus, [18F]FACBC is expected to be developed as a tumor diagnostic agent since it is largely taken up into tumor cells which are highly proliferative and active in protein synthesis.
In radioactive diagnostic imaging agents, a problem often arises such that compounds decompose by self-radiation during delivery of the agents so as to cause decrease in radiochemical purity due to so-called radiolysis. For general pharmaceuticals, it is recommended in the guideline of ICH that if decomposed matters in an agent exceed 1.0%, the decomposed matters be subjected to structure determination when the maximum daily dosage of an effective component thereof is as small as not more than 1 mg (Non-Patent Document 1). However, for radiopharmaceuticals low in a blended amount per se in the agent, in most cases, the physical amount of impurities resulting from the radiolysis in the agent is as small as about 10−12 mol, even if it exceeds 1.0%. Thus, it is very difficult to presume a structure of the decomposed matters, and to conduct verification as to whether or not the decomposed matters affect effectiveness such as tumor accumulation of the agent.
Also, particularly in radioactive diagnostic imaging agents, if impurities are generated due to decomposition, they often significantly affect the resulting image, even if the generated amount thereof is a small amount. Therefore, impurities in the radioactive diagnostic imaging agent should be maintained as low as possible, and it is preferable that radiolysis which may cause the production of impurities should also be inhibited as much as possible.
Various methods for inhibiting radiolysis have been examined focusing on application to [18F]fluoro-[18F]FDG).
International Publication No. WO03/090789 pamphlet discloses a method of reducing the radiolysis of [18F]FDG by adding a weak acid-based buffer to a [18F]FDG solution and an injection prepared by the method (Patent Document 1). Also, International Publication No. WO04/043497 pamphlet discloses adding ethanol to a [18F]FDG solution to obtain a composition for injection which may be (Patent Document 2).
Japanese Patent Laid-open (Kokai) No. H10-147542 discloses a technique utilizing an organic compound high in physiological acceptability such as monosaccharides, disaccharides, organic acids and salts or esters thereof as a radiation protecting agent (Patent Document 3). In this publication, the organic compound high in physiological acceptability and particularly effective as the radiation protecting agent is defined to have a reaction rate constant with OH radicals, H radicals or hydrated electrons in the range of 1×108 to 5×1010 mol−1s−1.
International Publication No. WO06/134822 pamphlet discloses a radioactive diagnostic imaging agent reduced in radiolysis by blending various sugar or sugar alcohol.
Non-Patent Document 1: Pharmaceutical Affairs Bureau Notification No. 0624001 (page 12)
Patent Document 1: International Publication No. WO03/090789 pamphlet
Patent Document 2: International Publication No. WO04/043497 pamphlet
Patent Document 3: Japanese Patent Laid-open (Kokai) No. H10-147542
Patent Document 4: International Publication No. WO06/134822 pamphlet